CN109963499A - For manufacturing the method with the capsule of absorbable event marker - Google Patents

Abstract

The various methods and apparatus for caning absorb capsule are proposed, the absorbable capsule includes the digital absorbable sensor element or absorbable sensor being embedded in capsule.Absorbable sensor element may be configured to activate when contacting with conductive fluid (such as gastric juice of body).Once being activated, absorbable sensor element may be configured to execute various tasks, such as transmits one or more signals and obtain the biological attribute data about the body for absorbing capsule.

Description

For manufacturing the method with the capsule of absorbable event marker

Cross reference to related applications

This application claims entitled " the METHODS FOR MANUFACTURING CAPSULES submitted on October 26th, 2016The beauty of WITH INGESTIBLE EVENT MARKERS (for manufacturing the method with the capsule of absorbable event marker) "The entire disclosure is incorporated into herein in general purpose by the priority of state's provisional application 62/413,397 hereinIn.

Background technique

Digital medical generally includes the electronic sensor component that some applications with drug are closely related, and allows to improveData tracking, such as the monitoring of more accurate compliance and various physiological signals.As medical industry is to the digital medical epochTransition, face practical challenge, such as how effectively and reliably digital sensor to be integrated in various drugs.

Summary of the invention

The various methods and apparatus for caning absorb capsule are proposed, the absorbable capsule includes the number being embedded in capsuleWord formula can absorb sensor element (or absorbable sensor).

In some embodiments, a kind of method of absorbable capsule of the manufacture including absorbable sensor is proposed.The partyMethod may include: the absorbable capsule that access has manufactured；Capsule is transformed into including absorbable using automatic manufacturing techniqueSensor, wherein absorbable sensor includes partial power, when partial power and conducting fluid contacts, which is canAbsorbing Sensor power supply.

In some embodiments of this method, capsule is transformed into including caning absorb sensor using automatic manufacturing techniqueIncluding use automatic manufacturing technique by absorbable sensor be wedged into capsule and using the edge of absorbable sensor with canAbsorbable sensor is affixed on capsule by the frictional force absorbed between the inner wall of capsule.

In some embodiments of this method, absorbable sensor includes at least part material, is configured to applyingIt is bent or deforms when physical pressure, and it includes by absorbable sensor wedge that wherein absorbable sensor, which is wedged into capsule,Make at least part bending or deformation of absorbable sensor when entering into capsule.

In some embodiments of this method, the material for being configured to be bent or deform is insoluble and nonconducting, andIt is also configured to the length by increasing the current path between two kinds of dissimilar materials for being located at absorbable sensor opposite sidesDegree is to amplify the signal from absorbable sensor emission.

In some embodiments of this method, capsule is transformed into including caning absorb sensor using automatic manufacturing techniqueIt include: that absorbable sensor is affixed in first band；By by the second band be affixed on absorbable sensor and first band withAbsorbable sensor is clipped between first band and the second band and forms absorbable sensor strip；And by being sensed absorbableDevice band is wrapped in capsule surroundings and absorbable sensor strip is affixed on capsule.

In some embodiments of this method, capsule is transformed into including caning absorb sensor using automatic manufacturing techniqueIt include: to be embedded in absorbable sensor on the inner wall of outer cap；And outer cap is affixed at least part of capsule, makeSensor must be can absorb to be clipped between at least part of capsule and outer cap.

In some embodiments of this method, capsule is transformed into including caning absorb sensor using automatic manufacturing techniqueIt include: the inner wall using the fixed capsule of fulcrum post；It is opposite with the inner wall of capsule supported by fulcrum post on the outer wall of capsule,Make a part deformation of the outer wall of capsule to form recess using deformation pin；And absorbable sensor is embedded in the recess of outer wallIn.

In some embodiments of this method, capsule is transformed into including caning absorb sensor using automatic manufacturing techniqueIt include: the inner wall that glueing material is applied to capsule；And absorbable sensor is fixed in capsule via glueing materialOn wall.In some embodiments of this method, glueing material includes at least one of following material: polyvinylpyrrolidone(PVP), hydroxypropyl cellulose (HPC), methylcellulose, ethyl cellulose, gelatin or hydroxypropyl methyl cellulose (HPMC).

In some embodiments of this method, capsule is transformed into including caning absorb sensor packet using automatic manufacturing processIt includes: deforming a part of capsule by applying heat to the part of capsule；And absorbable sensor is connected to glueThe deformed part of capsule.

In some embodiments of this method, capsule is transformed into including caning absorb sensor using automated manufacturing methodIncluding using fluidized bed coating to provide absorbable sensor pearl to capsule.

In some embodiments, the method that another manufacture includes the absorbable capsule of absorbable sensor is proposed.It shouldMethod can include: be partly formed absorbable capsule using automatic manufacturing technique；It will be can absorb using automatic manufacturing techniqueSensor is attached to the absorbable capsule of part formation；Using automatic manufacturing technique complete include absorbable sensor canThe formation of capsule is absorbed, wherein absorbable sensor includes partial power, when the partial power and conducting fluid contacts, the portionIndependent power source is absorbable sensor power supply.

It include that will can absorb by the capsule that absorbable sensor is attached to part formation in some embodiments of this methodIn the main body that sensor is wedged into the cap of capsule or part is formed, and utilize the edge of absorbable sensor and the cover of capsuleAbsorbable sensor is fixed to the cap of capsule to frictional force between the inner wall for the main body that cap or part are formed or part is formedMain body on.

In some embodiments of this method, absorbable sensor includes at least part material, which is configured toIt is bent or deforms when applying physical pressure, and absorbable sensor is wherein wedged into the cap of capsule or the master of part formationMake absorbable sensor when including in the main body that the cap or part that absorbable sensor is wedged into capsule are formed in bodyAt least part is bent or deformation.

In some embodiments of this method: being partly formed absorbable capsule includes making capsule material portion using forming pinDivide ground forming；Absorbable sensor is attached on the capsule of part formation includes: that absorbable sensor is placed on forming pinTip on；And absorbable sensor is embedded into the rounding end for the capsule that part is formed using the tip of forming pin；AndAnd the formation for completing absorbable capsule includes applying other capsule material on forming pin, so that absorbable sensor is via anotherAt least one surface attachment of outer capsule material not covered by forming pin.

In some embodiments of this method, absorbable sensor includes the rounding end with capsule with absorbable sensorThe matching surface of adjacent side relative positioning, the matching surface are configured to cooperate with the drug component to be filled into capsule.

In some embodiments of this method, the matching surface for caning absorb sensor includes spill.

In some embodiments of this method, the matching surface of absorbable sensor includes straight with two of acute angle connectionSide.

It include: to utilize material by the capsule that absorbable sensor is attached to part formation in some embodiments of this methodMaterial coats the side of the distal end towards partially formed capsule of the absorbable sensor, and the material is configured to: whenWhen the absorbable sensor is exposed to fluid, accelerate the separation of the absorbable sensor and the capsule distal end.

In some embodiments of this method, a part of capsule be constructed to it is insoluble so that when capsule is dissolved inWhen in fluid, the insoluble part of capsule remains attached on absorbable sensor and forms skirt around absorbable sensorPortion.

In some embodiments of this method, absorbable sensor is attached to part using automatic manufacturing technique and is formedAbsorbable capsule include: by quickly disintegrated material layer be casted into part formation absorbable capsule distal end in；It can inhaleSensor is received to be embedded into quickly disintegrated material layer；Insoluble material layer is casted on fater disintegration layer and is can absorb and is passedAround sensor；And be casted into the protected material bed of material can not be in soluble layer and absorbable sensor.

In some embodiments of this method, by absorbable sensor be attached to part formation capsule on include: canAbsorbing Sensor is placed in the distal portions of the capsule of part formation；And the formation for completing absorbable capsule includes by partThe capsule of formation is crimped on around absorbable sensor, so that absorbable sensor is fixedly secured to the distal portions of capsuleIt is interior.

Detailed description of the invention

In each figure of attached drawing, some embodiments are shown by way of example and not by way of limitation.

Fig. 1 shows the various exemplary geometries of absorbable sensor module of the frictional fit in capsule.

Fig. 2 shows the diagram with the capsule around surrounding band.

Fig. 3 shows the figure that how can be added to IEM in strapping.

Fig. 4 A-4B shows the multiple modifications that how can be molded into absorbable sensor in capsule.

Fig. 5 provides the example of double cap capsules including caning absorb sensor.

Fig. 6 provides the various figures of the different designs for being added to IEM or other absorbable sensor in capsule wallShow.

Fig. 7 A-7D provides the example of the digitlization capsule using molding or casting method.

Fig. 8 shows that via thermomechanical technology include the graphical representation of exemplary for caning absorb sensor capsule.

Fig. 9 A-9C shows the various examples for the technology being ejected into capsule using absorbable sensor as microballon.

Figure 10 shows the fluidized system for microballon concept.

Figure 11 A-11B provide it is in accordance with some embodiments during the manufacturing process of capsule how by sensor ball or pieceThe other example placed together with tablet or other mixtures.

Specific embodiment

In the following description, with reference to showing the attached drawing of several embodiments of the invention.It should be appreciated that not departing from this public affairsIn the case where the spirit and scope opened, it can use other embodiments and machinery can be carried out, composition, structurally and electrically operatedChange.It is described in detail below to be not be considered in a limiting sense, and the scope of embodiments of the invention is only by being announcedPatent claim limit.

Propose the various methods and method for caning absorb capsule, the capsule includes that be embedded in capsule digital canAbsorbing Sensor component or absorbable sensor.Absorbable sensor element can be configured to conductive fluid (such as bodyGastric juice) contact when activate.Once activation, absorbable sensor element may be configured to execute various tasks, such as transmitting oneOr the biological attribute data of multiple signals and acquisition about the body for absorbing capsule.The example of absorbable sensor element is that can inhaleReceive event marker (IEM) or Mini-IEM piece (MIT).Absorbable sensor herein alternatively referred to as sensor ball (SP),IEM and/or absorbable sensor microchip.Absorbable sensor includes the part electricity activated completely when with conducting fluid contactsSource, and be coupled to partial power and be configured to execute one or more functions to transmit data by the body for absorbing capsuleCircuit.As used herein, absorbable sensor element the process in capsule is added to be properly termed as making capsule " digitlization ".

In order to improve batch production and manufacture efficiency, it is desirable to create independent " number " capsule, then can be used inSo that any drug digitizes in the medicament capsule filling equipment of standard.Only IEM is put into capsule and will be led when drug is filledCause to need the customization at each contract manufacturer (CMO) or affiliate that production encapsulates digital drug to produce equipment in enormous quantities.This method may be costly, and may will limit the quantity that the interested CMO of digital drug is encapsulated to manufacture.

For making the digitized straightforward procedure of capsule, there may be problems.For example, absorbable sensor " loose " is putIt sets and allows it to move around in an uncontrolled fashion in capsule, this may influence equipment performance.In addition, loose inhalesReceiving sensor may also drop out from capsule in encapsulation process, so as to cause product quality problem.The various implementations of the disclosureAbsorbable sensor is fixed on known and controlled position by example.Many embodiments are described below, relate to how to make to inhaleCapsule digitlization is received, especially generally in accordance with the known fabrication techniques for generating absorbable capsule.

As described, some illustrative methods are provided for being that capsule addition can inhale after having manufactured capsuleThe method for receiving sensor --- manufacturing after capsule ---.These methods can be used for utilizing another automatic manufacturing technique --- itsUsing existing capsule manufacturing process --- to improve existing capsule.It also describes some for utilizing single manufacturing processAbsorbable sensor is added during capsule manufacture for capsule in illustrative methods.

Frictional fit can absorb sensor

In some embodiments, it can absorb sensor to be inserted into capsule in this way, i.e., by making absorbable sensingDevice and/or some parts of capsule cap or main body itself deform and hold it in appropriate location.This " frictional fit " footAbsorbable sensor to be maintained in capsule during the downstream transport of all digital drug manufactures and manufacturing step.

The geometry that absorbable sensor skirt section can be modified, a part to generate as insertion process is used for canAbsorbing Sensor is placed on the feature of bending or deformation in capsule.These features may include addition " corner ", " feeler lever " or singleThe pure inside dimension for making absorbable sensor skirt section be greater than capsule cap or main body.In general, around absorbable sensorSkirt section is made of insoluble non-conducting material, which effectively amplifies the signal from absorbable sensor transmissions.It is absorbableSensor usually passes through modulation electric current --- and it is by connecting two kinds of different materials positioned at the opposite sides for caning absorb sensorConductive fluid is formed --- to generate signal.Increase the length of current path using skirt material, to increase by electric current roadThe intensity for the signal that diameter is formed.Here, skirt material can also be used for providing friction, and absorbable sensor is securely wedged intoIn capsule.Same insoluble non-conducting material can also be flexible or deformable to a certain extent, curved to allowIt is bent --- the bending can increase frictional force.Fig. 1 shows absorbable sensor module various of the frictional fit in capsule and showsExample property geometry.Figure 105 shows an example of the cross section of capsule, wherein absorbable sensor is wedged into glueThe side of capsule.As shown, in this case, being bent or deforming to absorbable Sensor section, to be cooperated to the one of capsuleSide.This " frictional fit " keeps resting in capsule in which can help absorbable sensor stabilization, and prevent in supply chain orLoss during manufacturing activities.

Absorbable sensor 110,115,120,125,130,135 and 140, which is shown, can be used for providing " rubbing in capsuleThe other example of the geometry of wiping cooperation ".The center module shown in each example show can place it is absorbableThe position of sensor, and the material around absorbable sensor indicates insoluble and can be used for being swashed in absorbable sensorEnhance the skirt material of signal transmission capabilities when living.Absorbable sensor 110 shows standard size sensor.Absorbable sensingDevice 115 shows " oversize " sensor with big skirt section.Absorbable sensor 120 shows diamond shape skirt section.It is absorbableSensor 125 shows double leaf skirt section, and absorbable sensor 130 shows four salient angles around skirt section.Absorbable sensingDevice 135 with " feeler lever " configuration show two of skirt section it is long-armed, can be used for preventing absorbable sensor wedging stomach side wall orConductive fluid is needed to reach other regions of the opposite side of absorbable sensor.Sensor 140 includes the three arm structures for skirt sectionType, to further enhance these abilities.The post-processing that " frictional fit " method can be during manufacturing process and capsule manufacturesIt uses, which is integrated into absorbable sensor ball or piece in capsule during capsule manufacturing process, and capsule manufacturesPost-processing by existing capsule be transformed into including can absorb sensor.

Although all aspects of this disclosure, can suitable for the absorbable sensor being placed on capsule body or capAbsorbing Sensor, which is placed in the cap of capsule to reduce absorbable sensor and interfere in encapsulation process, is placed on capsuleThe risk of pharmaceutical mixture or tablet in main body.Capsule material can serve as the screen of pharmaceutical mixture/between pill and IEMBarrier.

Absorbable sensor capsule band

In some embodiments, absorbable sensor can be placed in the band of the main body of encapsulation capsule.Fig. 2 is shownThe diagram of capsule with the band around them.Absorbable sensor can be manufactured into cooperation in band.For generating bandIllustrative processes are known, for example, initially by Shionogi exploitation Quali-seal technique, Capsugel technique orR.P.Scherer Hardcapsule technique.It is made after the band that capsule surroundings are added can be the absorbable sensor capsule of additionThe example made.In addition, this can be the example for not needing to carry out mechanical change to capsule itself.This can permit certain capsules moreIt is easy to repack into including absorbable sensor, and/or certain capsule manufacturing process is allowed to be easily integrated absorbable sensor.

Fig. 3 provides the example how absorbable sensor being added in band, generates IEM's using standard film laminationBand.IEM 305 is clipped between belt 315 and 320.Furthermore it is possible to add such as loose or close material around IEM 305310 material is separated with improving IEM when contacting with fluid.The band can be compatible with existing lashing equipment.Standard can be usedRoll-to-roll web-handled manufacture tool generate strapping.The technique is usually by can precisely and rapidly assemble these componentsAutomatic machinery execute.The technique can permit adds absorbable sensor in a manner of manufacturing after capsule.

In this way it is possible to not need to be transformed the prior art for developing and filling capsule to combine absorbable passSensor.Then the technique can be applied to any band can cooperate the capsule in surrounding, to increase the absorbable sensing of additionThe generality of device.

Method molded sensor being attached on capsule

In some embodiments, IEM or sensor ball (SP) (for example, IEM in placebo tablet) are molded into capsule,So that it is kept during capsule formation via the drying or solidification of the capsule material directly contacted with sensor deviceIt is in place.This attachment method is enough that IEM/SP is maintained in capsule during all downstreams are transported with manufacturing step,To manufacture digital drug and keep unique orientation relative to capsule and subsequent drugloading rate.Building material for sensor ballIt can so select: not only optimize the adherency between coating procedure and sensor ball and capsule, but also be based on capsule configurationsMaterial (for example, gelatin, hydroxypropyl methyl cellulose or carrageenan) optimizes sensor performance.For example, bonding agent or disintegrating agentSelection can help to separate capsule and sensor under one's belt.

Fig. 4 A and 4B show a variety of modifications that how can be molded into absorbable sensor in capsule.As with Fig. 4 A mono-What is caused is used to for IEM being molded into the example process in capsule, and diagram 400, which is shown, to be formed using forming pin 405 with IEMThe front view of the process of capsule, and illustrate 430 and show its side view.Capsule forming pin 405, which will have, is processed into rounded tip410 vertical channel, shape are suitable for accommodating the IEM 420 vertically kept.By capsule material be applied to forming pin 405 itBefore, IEM 420 is placed in vertical channel 425, so that the circumference of IEM 420 is substantially flushed with the radius of rounded tip 410.It can include small vacuum ports 415 in forming pin 405, to help for IEM420 to be held in place.Then by glueCapsule material 455 is applied on the pin for keeping IEM, so that smooth outer surface and IEM are closely adhered on the edge part of its exposure(referring to diagram 450) around point.

As with Fig. 4 A and 4B it is consistent, for sensor ball to be molded into the example process in capsule, forming pinRounded tip is replaced by the tip geometry with a surface engagement of sensor ball.The matching surface of sensor ball can be withBe flat (referring to diagram 435), be configured to improve capsule forming process (referring to diagram 440 and 445), or recess with permitPerhaps tablet volume bigger in finished product number capsule.(multiple) non-matching surface of sensor ball can be shaped as imitating standard rubberThe rounded tip (this is useful for using normal capsules filling equipment) of capsule has custom geometric shapes with by capsuleIt divides into digital element, or has more obvious taper to enhance swallowing property.Then capsule material is applied to holdingOn the pin of sensor ball, so that smooth outer surface and sensor ball are via closely attached not by surface that forming pin covers?.

Fig. 4 B shows an example of assembled digital capsule, and wherein sensor ball 460 is attached to the one of tablet 465On end.In this example, the matching surface for being connected to tablet shapes in a concave manner.Then 460 He of sensor ball can be coatedThe combination of tablet 465 is to encase entire combination.In this example, second sensor ball 470 is connected to the opposite end of tablet 465, withIncrease power and function.In order to form taper capsule, as shown, can be applied in combination with vacuum ports 490 forming pin 475 withSensor ball 485 is pressed into the shape of restriction.Then tablet can be pressed against on sensor ball at matching surface.Capsule materialThe combination of the different components of 480 covering of material.

If forming pin must be immersed in the solution of capsule material, can by apply very slight vacuum comeIEM or sensor ball are maintained in forming pin.Alternatively, capsule can be the case where IEM or sensor ball be in stand up positionUnder (A and 4B referring to fig. 4) pass through spraying capsule material to forming pin on formed.

The technology for forming sensor for capsule is suitable for the cap and main part of capsule.

In this way, molding process can permit single step manufacturing process (that is, without attachment sensing after forming capsuleThe second process of device).In addition, the formula of molding process secures orientation of the sensor in capsule to realize predictable sensingDevice performance fixes orientation of the sensor in capsule body consistently to fill drug substance contents (that is, preventing sensorIt is mobile, thereby eliminate the potential air pocket that possibly can not fill drug), and sensor is fixed on capsule, so thatIt will not dislocate/remove during drug fills capsule.

Double-capsule with absorbable sensor

In some embodiments, capsule can be added in absorbable sensor by the capsulae vacuus of cap there are two design toolsIn, one of them (interior cap) will be entrenched in inside second (outer) cap to form fitting and leave enough spaces for inciting somebody to actionIEM or sensor ball are placed between two caps.The top section of interior cap can be shaped as it is slightly flat, with accommodateIEM or sensor ball.

Fig. 5 provides the example of double cap capsules including caning absorb sensor.IEM or sensor ball 505 can first byIt is placed in outer cap 510, then interior cap 515 can be snugly fitted in outer cap, thus fixed IEM or sensor ball505.Then capsule filling and process for preparation can be normally carried out according to required manufacturing technology, the main body until forming capsule520 rest part.Absorbable sensor, which is placed on, which reduces absorbable sensor disturbance between two caps of capsule, putsSet the risk of the pharmaceutical mixture or tablet in capsule body.This is in manufacturing after IEM or sensor ball to be added to capsuleAnother example without carrying out machine rebuilding to existing capsule.

Attach sensors to the method on capsule wall

In some embodiments, IEM or sensor ball are contained in the wall of capsule via one of following methods:

Casting or molding during capsule formation；

Pressure and/or temperature attachment；

It is press-fitted into the hole gone out in capsule；With

Bonding agent is fixed in the hole gone out in capsule.

Fig. 6 provides each of the different designs for being added to IEM 605 or other absorbable sensor in capsule wallKind diagram.The part of the capsule wall of fixed IEM circuit may include the capsule material 620 of standard or for enhancing IEM circuit functionThe material (for example, being similar to the material component for being currently used for the skirt section IEM of signal strength enhancing) of energy.

In the embodiment that an electrode surface of IEM integrated circuit is contacted with capsule wall, coating can be attached to capsuleIt is applied to IEM electrode surface before, to help for IEM circuit to be affixed on wall, and/or is being exposed to water/acidity present in stomachAccelerate the separation of IEM circuit and capsule material when condition.

In some embodiments, for casting/molding during capsule is formed, can will have similar to IEM circuitThe recess of shape be arranged on one end of forming pin 610.It can be picked up via vacuum and put device IEM circuit 605 is placed on recessIn.It can carry out positioning/holding of auxiliary circuit via the vacuum ports 615 on forming pin 610.Then via dip-coating, spraying orOther deposition techniques form capsule material on pin.Then the capsule with IEM circuit is removed from forming pin.It can will be multipleIEM circuit is placed in the main body and cap part of capsule for redundant signal transmission.

In some embodiments, for Pressure/Temperature adherence method, device tip 625 can be put by IEM circuit via picking up605 are pressed against on capsule wall, pick up put device tip 625 can apply it is enough heat or pressure circuit to be affixed on wall.It picks up and putsDevice tip 625 can be based on pressure or based on temperature.During applying heat and/or pressure, on being compressed against capsuleCircuit electrode surface near, capsule wall 620 can deform with it is thinning.When IEM 605 is pressed into capsule wall 620, branchConsigning 630 can provide setting for capsule wall 620.It can be via from picking up the heat transfer for putting device tip 625 or via non-contactMethod (for example, convection current, radiant heating) applies heat.Diagram 640 is shown IEM in the case where applying low temperature or low pressureThe example being placed on capsule, and diagram 650 shows and IEM is placed on capsule in the case where applying high temperature or high pressureExample.

In some embodiments, for press-fit adherence method, it is integrated that size ratio IEM is gone out in any surface of capsuleThe smaller hole of circuit.Then it puts device tip IEM circuit is put into hole via picking up, which applies enough pressure to push electricityIt is in place that road flushes ground in capsule wall.

In some embodiments, for bonding agent adherence method, hole is gone out in any surface of capsule.Pore size rangeCan from smaller (generate frictional fit to assist keeping) to it is bigger (separation permission circuit and wall or space, so as toBonding agent is filled to preferably keep).Then it puts manufacturing operation IEM circuit is placed in hole via picking up.Then by bonding agentIt is applied to the perimeter of circuit or covers entire circuit surface as drop.Used bonding agent can be via drying, solidChange, crosslinking or other effect means are formed.

In some embodiments, the part for being connected to absorbable sensor of capsule wall can be configured to be insoluble.The part can shape in some way, to increase alar part or skirt section around absorbable sensor.Therefore, when capsule wall is moltenXie Shi, insoluble skirt section and absorbable sensor will retain, and skirt section can amplify absorbable sensor signal in activationRange.

For circuit operation pick up put device tip can be kept based on vacuum or it is mechanical grasp, and may include putting simultaneouslyCircuits and the function of applying heat, pressure or bonding agent.

By using these any one of illustrative methods for being placed into absorbable sensor in capsule wall,Orientation of the sensor on capsule wall can be fixed to generate predictable sensor performance.In addition, the resistance of capsule volumePlug can be less, so that the drug products volume for allowing to fill in given capsule size is maximum.Moreover, these methods can be withSensor is fixed on capsule, so that sensor will not dislocate/remove during the drug filling of capsule.These and Fig. 6 phaseAssociated example is the other examples being integrated into IEM or sensor ball in capsule manufacturing process in capsule.Alternatively, with knotMode described in Fig. 6 is closed to be embedded in IEM or occur during sensor ball can manufacture after capsule.For example, can carry out across existingA part of capsule to form hole, to be embedded in the additional procedure of IEM or sensor ball.

With glued or molding sensor digital capsule

Since gelatin or hydroxypropyl methyl cellulose are the most frequently used materials for capsule, thus selection be it is restricted,Therefore it needs to customize absorbable sensor, so that it can be worked well in the capsule of these types.Glued or castingMaterial is the material that mold (absorbable sensor microchip), IEM or sensor ball are maintained to the appropriate location in capsule shellMaterial.Glued or founding materials component can be but not limited to polyvinylpyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylCellulose, ethyl cellulose, gelatin or hydroxypropyl methyl cellulose (HPMC).

In some embodiments, mold, IEM or sensor ball are remained attached to outside capsule by glued or founding materialsPosition inside shell.Then, which allows downstream to transport with manufacturing step to manufacture digital drug capsules product.

Fig. 7 A-7D shows how absorbable sensor can be attached on capsule 715 via glued or founding materials 705Various embodiments.In the case where glued or founding materials 705, hardening, solidification or dry, so that it is (absorbable by moldSensor microchip) 710, absorbable sensor or sensor ball be held in place.In the case where founding materials, it canFor use as skirt section to enhance sensor performance.

In some cases, glueing material 705 protects mold (absorbable sensor microchip) 710, IEM or sensor ballHold the appropriate location in capsule 715.The position can be located at the bottom of capsule shell, at either end above or on side wall, such asShown in various examples.The conceptual picture of three kinds of different digitlization capsules is shown in Fig. 7 A-7C.

Alternatively, mold can be placed on to the bottom of capsule, founding materials are then filled on it.Founding materials are not only usedIt is held in place in by mold, also serves as skirt section to improve sensor performance.

Glued or founding materials types can be various hydrogels or other formulateds to meet the poly- of required performanceCondensation material.

As a part (fixed amount is instilled into capsule half-shell by it) of manufacturing process, glued or founding materials amountsIt can be variation.Blobs of glue can be used by mold, IEM or sensor ball fix in position.

Can be cast by multiple layers in a manufacturing process, be related to not as being used as shown in example in Fig. 7 D for casting methodSame founding materials, wherein mold is sandwiched therebetween.The half of capsule shell 740, the layer packet of far-end are shown in fig. 7dInclude mold 730.Each layer can have unique function, such as the bottom 720 for quickly dissolving or being disintegrated, followed by the second skirt layer725, mold (the absorbable sensor of IEM or other) 730 is embedded, and is finally to protect the top layer 735 of sensor (referring to figure7D).This, which can be, is added to another example manufactured after capsule for IEM or sensor ball, and do not need to existing capsule intoRow machine rebuilding.Alternatively, can include as in conjunction with the example process described in Fig. 7 A-7D in capsule manufacturing process.For example, canIt is glued or with other sides absorbable sensor to be placed in capsule and is carried out before drug ingedient is filled into capsuleFormula attachment.

For absorbable sensor to be attached to the various mechanically or thermally mechanical means of capsule

In some cases, mechanically or thermally it is mechanically formed using and optionally come using bonding agent or thermomechanical processAbsorbable sensor is integrated to and is formd on capsule by absorbable sensor integration and is fixed on the method in capsule.

In some embodiments, it can absorb sensor to be inserted into capsule in this way, wherein increasing mechanically or thermally machineTool method can make a part deformation in the skirt section IEM to ensure to be fitted in capsule.In addition it is possible to use heat treatment canAbsorbing Sensor is attached on capsule.

As the example process for realizing this point, absorbable sensor is inserted into capsule in this way,Wherein increase mechanically or thermally mechanical means, a part deformation in absorbable sensor skirt section can be made to ensure to be fitted to capsuleIn.

In addition, heat treatment can be used for for absorbable sensor being attached on capsule.This can be in the appearance of medicament capsuleIt is carried out on face or inner surface.This can be real in the end (formed cone) of capsule or along the side (forming arch) of capsuleIt applies.It includes the graphical representation of exemplary for caning absorb the capsule of sensor that Fig. 8 is shown in this way.Capsule 805, which is shown, to be formed inThe example of IEM 810 outside capsule, and also show the IEM 815 for being formed in capsule.Pay attention to the curved of the skirt section of IEMBent structure.In some embodiments, a drop glue or other bonding agents 820 can also be increased to help the process.

It can be resisted against on capsule body and be formed, most probably use forming pin in capsule during formingOr other supporting members.Forming head will apply heat to IEM, and usually have and the matched required shape of attachment position on capsuleShape.

Alternatively, capsule attachment can be used bonding agent completion, such as under small edible glue point shown in figure.It can be withApply glue so that IEM is flushed or perpendicular to capsule surface adhered to.Capsule surface can preferably fix IEM without to circuitOn electrochemical layer add glue.

By using one of these methods, absorbable sensor can not needed for different glue from the integrated of capsuleIt is carried out in the method for capsule types/dimensions progress IEM being shaped, because forming can be when adhering to.Moreover, perpendicular to glueThe glue adherence method at capsule edge can guarantee and ensure electrochemical material far from gelatin materials to ensure to activate.This can beIEM or sensor ball are added in being manufactured after capsule and do not need another example for carrying out machine rebuilding to existing capsule.It or may include example process as described in conjunction with Fig. 7 A-7D in capsule manufacturing process.For example, absorbable sensor canTo be placed in capsule and be formed on capsule wall before drug component is filled into capsule.

Absorbable sensor pearl

In some embodiments, any existing capsule size, finished product glue can be made by adding IEM pearl to capsule to createThe digitized scheme of cap dosage.IEM pearl can be generated using the technology of referred to as fluidized bed coating.Fluidized bed (FB) coating can beSeveral functions/non-functional material layer is coated in substrate.The technology is commonly used in pharmaceuticals industry to coat excipient substrate (pearl).

Three kinds of modifications of spraying technique: top spray (Fig. 9 A) can be used；Spray (Wurster Column) (Fig. 9 B) in bottom；The side andIt sprays (Fig. 9 C).

IEM (exposed, not have ethyl cellulose skirt section) or other absorbable sensor microchips can serve as basic baseBottom can be applied coated with function/non-functional coating material in fluidized bed coating process device, to assign IEM specific character.Figure 10FB system demonstrate this concept.Then, other than drug payload, the IEM (IEM pearl) of coating can be instilled into glueIn capsule.IEM pearl will be designed to activate quickly after it interacts with gastric juice, and drug (particle, ball etc.) can be pre- according to itsPhase design works independently of IEM.

It is taken as an example of this method, basic mold can be obtained from the subset of present production process (without skirtThe absorbable sensor microchip of portion's material).Then basic mold can be used in FB coat system to assign function/non-functionalCoating.Then the pearl of coating can be added in a large amount of capsule formulations is proved with establishing concept.This, which can be, is added to IEMIn manufacturing after capsule and another example that machine rebuilding is carried out to existing capsule is not needed.

Other adherence method

Figure 11 A and 11B provide it is in accordance with some embodiments during the manufacturing process of capsule can how with tablet orOther mixtures place the other example of sensor ball or piece together.In Figure 11 A, tablet 1110 is shown at capsule materialThe centre of material, and two sensor balls or piece 1105 and 1115 are located at distal end.Show piece 1105 and 1115, and IEM1120 quiltAlternative exemplary as the absorbable sensor for being located at capsule distal end is shown.Capsule can be initially formed two-piece type, such as upper halfPortion and lower half.Sensor ball or piece can be pre-loaded into the distal end of capsule material during manufacturing process.It is then possible to fill outFill tablet.As some examples, frictional fit, gluing or coating may then pass through to connect two half-unit.

Figure 11 B show it is in accordance with some embodiments can how fixed by sensor ball or piece 1130 during manufacturing processTo another example of the remote location of capsule material.Capsule material can be around the formation of sensor 1130, to pass in distal endSensor lock into place, as shown in the figure.Just can be enough to be consolidated in a small amount of crimping 1125 of the near top of sensor ball or pieceSurely the distal end of capsule material is arrived.Then, drug material can be filled into the rest part of capsule.

In some embodiments, absorbable sensor can be applied to is placed on inserting at the top of capsule body after fillingPlug.The main body of capsule may include medicament, and main body is fastened in capsule compartment by plug together with absorbable sensor.Work as capsuleWhen dissolving in gastric juice, IEM can be detached from plug, so as to activate.In some embodiments, sensor ball plug can beEnd is attached in capsule cap, which is formed without dome or removes dome upon formation.Plug withAdherence method between cap can be frictional fit, bonding agent attachment or heat attachment.Then, this to have sensor ball plugCap will be handled on the capsule filling equipment of standard.

In some embodiments, using the rapid release layer and individual machine between IEM and Solid oral pharmaceutical outer surfaceTool attachment material limits adherence method on piece or capsule.Releasing layer makes the phase between the drug products material and IEM of dissolutionInteraction minimizes, so that it is guaranteed that release and IEM activation, and individually attachment (hand can also be used other than releasing layerSection) to obtain mechanical strength.Mechanical attachment will be generally located on the outside of releasing layer, but be not required.The example of displaying includesUse the low melting point grease in the covering activity region IEM as releasing layer, and the HPC glue around periphery adheres to obtain machineryIntegrality.Heat attachment in periphery can also be used together with releasing layer.Releasing layer can be soluble material or can be fusibleGrease, and can be used as thin film component distribution printing or place.Separation for mechanical attachment and the material of release is permittedPerhaps the attachment design being resistant to more extensively, and it is unrelated with the surface of oral drugs product or dissolution characteristic.It can be used for dischargingVarious distribution, printing or the film figure of layer and both adhesive layers carry out adjusting property.

In some embodiments, in feasible situation, disclosed method may include the skirt around absorbable sensorPortion's material.The material can be configured to expand during activation.Expansion can behave like the jellyfish expanded in water or pictureThe paper folding for initially being wrinkled or being compacted and then expanding it.In other cases, skirt section can via absorbable sensor withThe bubble that generates when conductive fluid reacts and expand.Other expanding methods include being added to have different heat expansion rate on skirt sectionLayer, or it is different from each other with the interaction of the surface tension of water or other conductive fluids.

In some embodiments, disclosed method may include pre-constructed unit, can be attached during standard manufacturing processTo on various capsule articles.For example, can according to any method described herein by modified cap or with manufacture at include canThen these parts can be replaced normal capsules component and are integrated in capsule manufacturing process by Absorbing Sensor.

Unless expressly stated otherwise, otherwise such as " processing " used herein, " operation ", " calculating ", " determination ", " be inNow ", the discussion of the words such as " display " can refer to the movement or process for calculating equipment 1100 (for example, computer), the calculating equipmentManipulation is converted in one or more memories (for example, volatile memory, nonvolatile memory or its any suitable groupClose), register or reception, storage, transmission or show be expressed as in other calculating parts of appliance of information physics (for example, electronics,Magnetically or optically) the data measured.In addition, unless stated otherwise, otherwise as common in the patent literature, make hereinIt include one or more than one example with term "a" or "an".Finally, it is as used herein, unless stated otherwise,Otherwise conjunction "or" refers to the "or" of nonexcludability.

Although flow chart described herein and method can describe specific to execute sequence, it should be appreciated that, executionSequence can be different from described sequence.Two or more moulds are executed for example, can upset relative to described sequenceThe sequence of block or step.Moreover, two or more modules or step can be performed simultaneously or partially simultaneously.In addition,In some embodiments, one or more modules or step can be skipped or omitted.It should be understood that all these variations are all in the disclosureIn the range of.

The disclosure is illustrative and be not restrictive.It is emphasized that above-described embodiment of the disclosure is only to beThe possibility example of embodiment for being expressly understood the principle of the disclosure and illustrating.Not substantially be detached from the disclosure spirit andIn the case where principle, can to above-described embodiment many modifications may be made and remodeling.According to the disclosure, further modification is for thisIt will be apparent, and be intended to come within the scope of the appended claims for the technical staff of field.

Claims (22)

1. a kind of manufacture includes the method for the absorbable capsule of absorbable sensor, this method comprises:

Access the absorbable capsule manufactured；And

Capsule is transformed into including caning absorb sensor using automatic manufacturing technique,

Wherein, the absorbable sensor includes partial power, when the partial power and conducting fluid contacts, the partPower supply is the absorbable sensor power supply.

2. according to the method described in claim 1, wherein, capsule being transformed into using automatic manufacturing technique and is passed including absorbableThe step of sensor includes: to be wedged the absorbable sensor in the capsule and described in utilization using automatic manufacturing techniqueThe absorbable sensor is affixed to by the frictional force between the edge of absorbable sensor and the inner wall of the absorbable capsuleOn the capsule.

3. according to the method described in claim 2, wherein, the absorbable sensor includes at least part material, the materialMaterial is configured to be bent or deform when applying physical pressure, and wherein wedges the absorbable sensor in the capsuleStep includes: to make at least part of the absorbable sensor curved when the absorbable sensor is wedged into the capsuleBent or deformation.

4. according to the method described in claim 3, wherein, the material for being configured to be bent or deform is insoluble and does not leadElectricity, and be also configured to by increasing the shape between the two kinds of different materials of opposite sides for being located at the absorbable sensorAt the length of current path amplify the signal from the absorbable sensor emission.

5. according to the method described in claim 1, wherein, capsule being transformed into using automatic manufacturing technique and is passed including absorbableThe step of sensor includes:

Absorbable sensor is affixed in first band；

It brings up by the way that the second band is affixed on the absorbable sensor and described first and is clipped in the absorbable sensorTo form absorbable sensor strip between the first band and second band；And

The absorbable sensor strip is affixed to institute by the way that the absorbable sensor strip is wrapped in the capsule surroundingsIt states on capsule.

6. according to the method described in claim 1, wherein, capsule being transformed into using automatic manufacturing technique and is passed including absorbableThe step of sensor includes:

The absorbable sensor is embedded on the inner wall of outer cap；And

The outer cap is affixed at least part of the capsule, so that the absorbable sensor is sandwiched in the glueBetween at least part of capsule and the outer cap.

7. according to the method described in claim 1, wherein, capsule is transformed into and passes including absorbable by the automatic manufacturing techniqueThe step of sensor includes:

Use the inner wall of the fixed capsule of fulcrum post；

It is opposite with the inner wall of capsule supported by the fulcrum post on the outer wall of the capsule, make the glue using deformation pinA part deformation of the outer wall of capsule is to generate recess；And

The absorbable sensor is embedded in the recess of the outer wall.

8. according to the method described in claim 1, wherein, capsule being transformed into using automatic manufacturing technique and is passed including absorbableThe step of sensor includes:

Glueing material is applied on the inner wall of the capsule；And

The absorbable sensor is fixed on the inner wall of the capsule via glueing material.

9. according to the method described in claim 8, wherein, the glueing material includes at least one of following material: poly- secondAlkene pyrrolidone (PVP), hydroxypropyl cellulose (HPC), methylcellulose, ethyl cellulose, gelatin or hydroxypropyl methyl fiberPlain (HPMC).

10. according to the method described in claim 1, wherein, capsule is transformed into including absorbable using automatic manufacturing techniqueThe step of sensor includes:

The part of the capsule is deformed by applying heat to a part of the capsule；And

The absorbable sensor is attached on the deformed part of the capsule.

11. according to the method described in claim 1, wherein, capsule is transformed into including absorbable using automatic manufacturing techniqueThe step of sensor includes: to apply absorbable sensor pearl to the capsule using fluidized bed coating process.

12. a kind of method that manufacture includes the absorbable capsule of absorbable sensor, which comprises

The absorbable capsule is partly formed using automatic manufacturing technique；

The absorbable sensor is attached on the absorbable capsule being partly formed using automatic manufacturing technique；WithAnd

It joined the formation of the absorbable capsule of the absorbable sensor using automatic manufacturing technique completion,

Wherein, the absorbable sensor includes partial power, when the partial power and conducting fluid contacts, the partPower supply is the absorbable sensor power supply.

13. according to the method for claim 12, wherein the step being attached to absorbable sensor on the capsule of part formationSuddenly include: by the absorbable sensor be wedged into the capsule cap or part formed main body in, and utilize described in canFrictional force between the inner wall for the main body that the cap of the edge of Absorbing Sensor and the capsule or part are formed by it is described canIn the main body that Absorbing Sensor is fixed to the cap of the capsule or part is formed.

14. according to the method for claim 13, wherein the absorbable sensor includes at least part material, describedMaterial is configured to be bent or deform when applying physical pressure, and the absorbable sensor is wherein wedged into the capsuleThe cap or part formed main body in step include: to be wedged into the cap of the capsule in the absorbable sensorOr at least part of the absorbable sensor is made to be bent or deform when in the main body of part formation.

15. according to the method for claim 12, in which:

The step of being partly formed the absorbable capsule includes: using forming pin partly shaped capsules material；

By absorbable sensor be attached to part formation capsule on step include:

The absorbable sensor is placed on the tip of the forming pin；With

The absorbable sensor is embedded into using the tip of the forming pin in the rounding end of the capsule of part formation；And

The step of completing the formation of absorbable capsule includes: to apply other capsule material on the forming pin, so that describedAbsorbable sensor adheres to via at least one surface for the additional capsule material not covered by the forming pin.

16. according to the method for claim 15, wherein the absorbable sensor includes matching surface, the cooperation tableFace is relatively positioned with the side adjacent with the rounding end of the capsule of the absorbable sensor, the matching surface constructionCooperate at the drug ingedient to be filled in the capsule.

17. according to the method for claim 16, wherein the matching surface of the absorbable sensor includes spill.

18. according to the method for claim 16, wherein the matching surface of the absorbable sensor includes being connected with acute angleTwo straight flanges.

19. according to the method for claim 12, wherein the step being attached to absorbable sensor on the capsule of part formationSuddenly include:

The side of the distal end towards partially formed capsule of the absorbable sensor, the material are coated using materialIt is configured to: when the absorbable sensor is exposed to fluid, accelerating point of the absorbable sensor and the capsule distal endFrom.

20. according to the method for claim 12, wherein a part of the capsule be constructed to it is insoluble so that working asCapsule dissolution in a fluid when, the insoluble part of the capsule remain adhered on the absorbable sensor andSkirt section is formed around the absorbable sensor.

21. according to the method for claim 12, wherein absorbable sensor is attached to portion using automatic manufacturing techniquePoint formed absorbable capsule the step of include:

Quickly disintegrated material layer is casted into the distal end of partially formed absorbable capsule；

The absorbable sensor is embedded into the quickly disintegrated material layer；

Insoluble material layer is casted on fater disintegration layer and is located at around the absorbable sensor；And

The protected material bed of material is casted into can not be in soluble layer and on the absorbable sensor.

22. according to the method for claim 12, in which:

The step absorbable sensor being attached on the capsule of part formation includes::

The absorbable sensor is placed in the distal portions of partially formed capsule；And

The step of completing the formation of absorbable capsule includes: around the absorbable sensor by partially formed glueCapsule crimping, so that absorbable sensor is securely fastened in the distal portions of the capsule.